Many hormones and neurotransmitters control functions of the body through specific receptors present in the cellular membrane. Many of these receptors perform intracellular signal transduction by activation of coupled guanine nucleotide-binding proteins (hereinafter to be abbreviated as G protein). Moreover, since these receptors have a common structure having a 7-transmembrane domain, they are generically referred to as G protein-coupled receptors or 7-transmembrane receptors.
As one of these G protein-coupled receptor proteins, a human receptor protein encoded by GPR54 gene is known [non-patent document 1].
In addition, as a bioactive peptide functionable as a ligand for the above-mentioned GPR54, metastin (aka kisspeptin) is known [non-patent document 2].
Cancer metastasis is a key factor that determines the life expectancy of patients. Metastin acting as a GPR54 agonist is known to suppress metastasis of lung transitional GPR54-expressing melanoma [non-patent document 2].
Likewise, it has been clarified that metastin also suppresses metastasis of GPR54-expressing pancreatic cancer cells [non-patent document 3]. On the other hand, it has recently been clarified one after another that release of sex hormone such as gonadotropin and the like when agonist acts on intracerebral GPR54 [non-patent document 4], and loss of function of GPR54 causes deficiency of sexual function [non-patent document 5]. As mentioned above, the metastin/GPR54 system is a highly attractive drug discovery target for both the suppression of cancer metastasis and sexual functional diseases.
The present inventors have found that a pentapeptide derivative having a bis-2-picolylamino group or a guanide group as a basic functional group at the N-terminal is a GPR54 agonist [non-patent document 6]. In addition, they have found that a ligand having a 4-fluorobenzoyl group at the N-terminal shows the highest bioactivity from among the compounds reported to show an agonist activity, and obtained information relating to the structure and activity thereof by conducting studies of the quantitative structure-activity relationship [non-patent document 7]. Furthermore, they have found that pentapeptide modified to have, at the N-terminal, (i) an aryl group or an aryl group having electron-withdrawing properties as a whole, (ii) a substituted or unsubstituted aromatic heterocyclic group containing at least one kind of hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or (iii) an aryl group substituted by 1 to 3 electron-donating groups selected from the group consisting of a lower alkoxy group, a hydroxy lower alkyl group, an amino lower alkyl group, a lower alkanoylamino lower alkyl group, a hydroxy-substituted phenylcarbonyloxy group, an amino group and a hydroxyl group has superior GPR54 agonist activity [patent document 1].
On the other hand, metastin-related peptide has been reported to show decomposition of a peptide bond between Gly-Leu dipeptides on the C-terminal by plural matrix metalloproteinases (MMP), and a combined use with an MMP inhibitor or use of a metastin derivative free of decomposition by MMP is suggested to be necessary in consideration of the clinical application of metastin-related peptide [non-patent document 8].